The compounds prepared by the process of this invention are .alpha.-arylalkanoic acid derivatives of the general formula ##STR1## and are characterized by having an aryl and an alkyl group at the .alpha.-position. In the formula, Ar represents an aryl of 6-13 carbon atoms and is an optionally substituted phenyl, phenoxyphenyl, naphthyl, biphenyl group or amino-substituted phenyl group; R.sup.6 is hydrogen or C.sub.1-4 alkyl group.
For almost a century, aspirin has dominated as a mild anti-inflammatory, analgesic and antipyretic agent. Over the last twenty years there has been great demand for aspirin-like drugs having higher therapeutic response and less side effects than aspirin itself. .alpha.-Arylalkanoic acids, particularly the .alpha.-arylpropionic acids, have already proven to be suitable compounds to fulfill these requirements. In fact, some of them, like Fenoprofen, Naproxen (S) and Ibuprofen have already been extensively used in medical practice. Their therapeutic effects were related to the inhibitation of prostaglandin biosynthesis. These compounds have valuable anti-inflammatory, analgesic and antipyretic properties. Clinical efficacy has been demonstrated in rheumatoid arthritis and osteoarthritis. Furthermore, in general, the compounds exhibit low toxicity and low irritancy to the gastric mucosa; they do not have other undesirable pharmacological activities which might give rise to unwanted side effects. Hence, the need has arisen for new and improved, economical synthetic procedures suitable for their preparation and manufacture on an industrial scale.
Conventional methods for producing these pharmaceuticals are complicated and industrially disadvantageous. Typical reported methods for producing Fenoprofen [2-(3-phenoxyphenyl)propionic acid] are:
(1) The method of U.S. Pat. No. 3,600,437 which comprises sodium borohydride reduction of m-phenoxyacetophenone to .alpha.-(m-phenoxyphenyl)-ethyl alcohol, reaction with phosphorus tribomide to form .alpha.-(m-phenoxyphenyl)ethyl bromide, displacement of the bromine with sodium cyanide in dimethyl sulfoxide, followed by hydrolysis with sodium hydroxide to furnish the desired .alpha.-(m-phenoxyphenyl)propionic acid. This method is disadvantageous in that the product is prepared in a multi-step synthesis which involves the use of m-phenoxyacetophenone as a starting material, which in turn is obtained from m-hydroxyacetophenone via the coupling reaction with bromobenzene catalyzed by a copper catalyst. Due to the meta-orientation of the hydroxy group, m-hydroxyacetophenone cannot be obtained directly by simple procedures and is expensive. The m-phenoxy-2-phenethylbromide intermediate is unstable and creates problems in mass production. Moreover, the process necessitates the use of sodium cyanide which is extremely poisonous and undesirable from a safety viewpoint.
(2) The method of Japanese Pat. No. 45586/76 CA 75:48707m (1971) which comprises bromination of m-methyl diphenyl ether with N-bromosuccinimide to form m-(bromomethyl)diphenyl ether, displacement of the bromine with sodium cyanide in dimethylsulfoxide to form m-(cyanomethyl)diphenyl ether, hydrolysis followed by esterification to give ethyl .alpha.-(m-phenoxyphenyl)acetate, conversion to form diethyl 2-(m-phenoxyphenyl)malonate by reacting the ester with diethyl carbonate and sodium, methylation with methyl iodide to furnish diethyl 2-methyl-2-(m-phenoxyphenyl)malonate, and finally, hydrolysis followed by decarboxylation to obtain the product .alpha.-(m-phenoxyphenyl)propionic acid.
This method is also laborious, involving the introduction and removal of a carboxyl group, the use of N-bromosuccimide, an expensive reagent, and also the use of the poisonous cyanide reagent.
Conventional reported methods for producing Ibuprofen [2-(4-isobutylphenyl)propionic acid] are:
(1) The method of British Pat. No. 971,700/64 and Japanese Pat. No. 7491/65 which comprises the conversion of a p-isobutylphenylacetic acid ester by the action of dialkyl carbonate in the presence of a base to form the corresponding malonic ester, methylation of the malonic ester with methyl iodide, hydrolysis and subsequent removal of the carboxyl group through pyrolysis to afford the desired propionic acid.
(2) The method of Japanese Pat. No. 18105/72 which comprises the reaction of p-isobutylacetophenone with potassium cyanide and ammonium carbonate to form the corresponding hydantoin, hydrolysis of the hydantoin to obtain an .alpha.-amino acid, alkylation to give dialkylamino product, and finally hydrogenation to furnish 2-(4-isobutylphenyl)-propionic acid.
(3) The method of Japanese Pat. No. 24550/72 CA 72:21492p (1970) which comprises the reaction of p-isobutylacetophenone with a monochloroacetic acid ester under the Darzen reaction conditions to obtain the corresponding epoxycarboxylic acid ester, hydrolysis and decarboxylation to afford .alpha.-(p-isobutylphenyl)propionaldehyde, and then oxidation to give the desired propionic acid.
(4) The method of European Pat. No. 34871/81; CA 96(5):34940d (1981) which comprises the rearrangement of alpha-haloketals of p-isobutylacetophenone in the presence of a Lewis acid.
These methods are industrially disadvantageous in that they involve multi-step reactions and all start from isobutylacetophenone which is prepared through acylation of isobutylbenzene under Friedel-Crafts reaction conditions with aluminum chloride. The mass amount of aluminum hydroxide formed during a normal workup usually creates an isolation problem for the product and, furthermore, it imposes a waste disposal problem.